About FANCL
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
FANCL c.580A>G, p.(Ile194Val)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 0
Benign evidence criteria: 1
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence uniformly predict no impact on the gene product. REVEL score 0.049 (strongly benign-predicting), BayesDel score -0.583 (benign-predicting), and SpliceAI max delta 0.00 (no predicted splicing impact). All available in silico tools support a benign interpretation.
Recorded classification: Uncertain significance
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BP4 supporting benign; combination = 1 supporting benign, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
235 / 1,614,080 alleles
gnomAD v4.1: 235 / 1,614,080 alleles. Recorded AF 0.000145594. Recorded homozygote count 1.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00024047; MAF= 0.02405%, 68/282780 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.00153535; MAF= 0.15353%, 47/30612 alleles, homozygotes = 0); grpmax FAF= 0.00118549.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
No listed criterion applied
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
2 reported laboratory submissions
2 Uncertain significance.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. FANCL, an E3 ubiquitin ligase involved in DNA repair, is infrequently altered in cancer. Germline mutations of FANCL are associated with the cancer pr
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
29 criteria with recorded statuses: 1 met · 16 not met · 6 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_018062.3:c.580A>G (p.Ile194Val) is a missense variant in exon 8 of FANCL, a Fanconi anemia pathway gene.
This variant is present in population databases: 68 of 282,780 alleles in gnomAD v2.1 (AF 0.024%) and 235 of 1,614,080 alleles in gnomAD v4.1 (AF 0.015%), including one homozygous individual in v4.1.
Multiple in silico predictors support a benign effect: REVEL score 0.049, BayesDel score -0.583, and SpliceAI max delta score 0.00.
The variant has been reported in ClinVar as Uncertain significance by two clinical laboratories (Labcorp Genetics, Fulgent Genetics) with no expert panel classification.
No variant-specific functional studies, case-control data, de novo observations, or segregation data are available.
The only criterion met is BP4 (supporting benign) based on consistent in silico predictions of no impact.
Applying generic ACMG/AMP 2015 combination rules (PMID:25741868): a single supporting benign criterion (BP4) is insufficient to classify as likely benign. The variant remains a variant of uncertain significance.
No criteria match.
Met · 1
BP4 SupportingMultiple lines of computational evidence uniformly predict no impact on the gene product. REVEL score 0.049 (strongly benign-predicting), BayesDel score -0.583 (benign-predicting), and SpliceAI max delta 0.00 (no predicted splicing impact). All available in silico tools support a benign interpretation. Details ▾Hide ▴
Evidence considered
- REVEL 0.049 (benign
- well below 0.5 threshold)
- BayesDel -0.583 (benign
- well below 0.0 threshold)
- SpliceAI max delta 0.00 (no splice alteration predicted)
Sources
Not met · 16 · evaluated, threshold not reached
PS1 PS1 requires a different nucleotide change at the same codon that produces the same amino acid change and is known to be pathogenic. No alternative nucleotide substitution at c.580 resulting in p.Ile194Val has been identified or reported as pathogenic. Details ▾Hide ▴
Evidence considered
- No alternative nucleotide change at codon 194 identified
PS3 No variant-specific functional studies were identified. In silico predictors (REVEL 0.049, BayesDel -0.583) uniformly predict a benign effect. OncoKB reports no reviewed functional evidence for this variant. Details ▾Hide ▴
Evidence considered
- REVEL score 0.049 (benign-predicting)
- BayesDel score -0.583 (benign-predicting)
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional evidence
Still missing
- No in vitro or in vivo functional assays performed for this variant
Sources
PS4 No case-control studies or statistical enrichment data are available for this variant. The variant has been reported in ClinVar as Uncertain significance by two clinical laboratories, but no case counts or odds ratios are provided. Details ▾Hide ▴
Evidence considered
- ClinVar classification: Uncertain significance
- 2 clinical laboratories
- no case-control data
Still missing
- No case-control study or statistical comparison of affected vs. unaffected individuals
Sources
PM1 Residue 194 is not located within a statistically significant mutational hotspot and does not lie in a well-established functional domain where pathogenic variants cluster and benign variants are absent. Details ▾Hide ▴
Evidence considered
- Hotspots analysis: residue not statistically significant
- exact variant not listed in hotspot regions
PM2 This variant is present in population databases. In gnomAD v2.1, it is observed in 68 of 282,780 alleles (AF 0.024%) with highest subpopulation frequency of 0.154% in South Asian. In gnomAD v4.1, it is observed in 235 of 1,614,080 alleles (AF 0.015%) including one homozygous individual. The South Asian subpopulation frequency (0.15%) exceeds the 0.1% threshold for PM2. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 68/282
- 780 alleles
- SAS AF 0.154%
- gnomAD v4.1: 235/1
- 614
- 080 alleles
- 1 homozygote
- SAS AF 0.138%
Sources
PP3 Multiple in silico predictors uniformly suggest a benign effect. REVEL score is 0.049 (benign-predicting, well below typical PP3 threshold of >0.5). BayesDel score is -0.583 (benign-predicting). SpliceAI predicts no splicing impact (max delta score 0.00). No computational tool supports a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL 0.049 (benign)
- BayesDel -0.583 (benign)
- SpliceAI max delta 0.00 (no splicing impact)
Sources
PP5 PP5 requires a reputable source to have classified the variant as pathogenic. ClinVar reports this variant as Uncertain significance by two clinical laboratories (Labcorp Genetics, Fulgent Genetics). No expert panel or reputable source has classified this variant as pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar: Uncertain significance
- 2 clinical laboratories
- no expert panel classification
Sources
BA1 BA1 requires an allele frequency >1% in any general population. The highest observed population frequency is 0.154% in the South Asian subpopulation (gnomAD v2.1), which is well below the 1% threshold. Details ▾Hide ▴
BS1 BS1 requires an allele frequency >0.3% for a disorder expected to be rarer than the observed frequency. The highest observed population frequency is 0.154% in South Asian (gnomAD v2.1), below the 0.3% threshold. The single homozygote in gnomAD v4.1 is noted but does not independently satisfy BS1. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 SAS AF 0.154% (below 0.3% threshold)
- gnomAD v4.1: 1 homozygote observed
Still missing
- Borderline SAS population frequency
- 1 homozygote in v4.1 raises suspicion but AF remains below 0.3%
Sources
BS2 BS2 requires observation in a healthy adult homozygous state for a fully penetrant recessive disorder with early onset. One homozygous individual is present in gnomAD v4.1, but a single observation in a population database without clinical confirmation is insufficient to meet BS2. Additional homozygous observations or confirmed healthy adult status would be required. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: 1 homozygote (235 total alleles)
- insufficient for BS2
Still missing
- Single homozygote without clinical confirmation of healthy adult status
- additional homozygous observations needed
Sources
BS3 BS3 requires well-established in vitro or in vivo functional studies demonstrating no damaging effect. No variant-specific functional assays are available. In silico predictions (REVEL 0.049, BayesDel -0.583) suggest a benign effect but do not constitute well-established functional studies. Details ▾Hide ▴
Evidence considered
- REVEL 0.049 (benign-predicting
- not a functional assay)
- BayesDel -0.583 (benign-predicting
- OncoKB: no functional evidence available
Still missing
- No variant-specific functional assay data (e.g.
- FANCD2 monoubiquitination
- MMC sensitivity)
Sources
BP1 BP1 applies to missense variants in genes where only truncating variants cause disease. FANCL is a Fanconi anemia gene in which missense variants are a known pathogenic mechanism, including documented founder missense variants in the South Asian population. BP1 does not apply. Details ▾Hide ▴
Evidence considered
- FANCL: both missense and truncating variants are established disease mechanisms
- South Asian founder missense variant documented
- missense variants are not a benign-only class in this gene
Sources
pvs1_gene_context
BP2 BP2 requires observation in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant. No phasing data are available for this variant. Details ▾Hide ▴
Evidence considered
- No phasing or co-occurrence data available
Still missing
- No cis/trans phasing data with known pathogenic variants
BP5 BP5 requires identification of an alternate molecular basis for disease in a case harboring this variant. No data are available regarding alternate molecular diagnoses in individuals carrying this variant. Details ▾Hide ▴
Evidence considered
- No alternate molecular cause identified
Still missing
- No data on alternate diagnoses in carriers
BP6 BP6 requires a reputable source to classify the variant as benign. ClinVar reports this variant as Uncertain significance. No clinical laboratory or expert panel has classified it as benign or likely benign. Details ▾Hide ▴
Evidence considered
- ClinVar: Uncertain significance
- no benign classification by any submitter
Sources
PS5 PS5 requires a different pathogenic missense change at the same amino acid residue. No pathogenic missense variant at codon 194 (Ile194) has been identified in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
- PM5 candidate search found no same-residue comparator variants
Sources
pm5_candidates
Not assessed · 6 · no assessment recorded
PS2 No de novo data are available for this variant. Confirmed de novo occurrence requires parental testing with confirmed maternity and paternity. Details ▾Hide ▴
Still missing
- No trio or parent-of-origin data available
PM6 No de novo data are available for this variant. PM6 requires confirmed de novo occurrence with maternity and paternity confirmed. Details ▾Hide ▴
Still missing
- No trio or parent-of-origin data available
PP1 No segregation data are available for this variant. PP1 requires cosegregation with disease in multiple affected family members. Details ▾Hide ▴
Still missing
- No family or segregation data available
PP2 Insufficient gene-level constraint data are available to determine whether FANCL has a low rate of benign missense variation. PP2 requires gene-specific missense constraint metrics (e.g., missense z-score) that are not available in this assessment. Details ▾Hide ▴
Still missing
- No missense constraint z-score or gene-level benign missense rate data available
PP4 No specific patient phenotype information is available for independent evaluation. While FANCL is associated with Fanconi anemia, PP4 requires detailed phenotypic data supporting the specific diagnosis in the proband. Details ▾Hide ▴
Still missing
- No patient phenotype
- clinical history
- or physical findings available
BS4 No segregation data are available. BS4 requires lack of cosegregation with disease in affected family members. Details ▾Hide ▴
Still missing
- No family or segregation data available
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 applies only to null variants (nonsense, frameshift, canonical splice). NM_018062.3:c.580A>G is a missense variant (p.Ile194Val) in exon 8 and is not predicted to cause loss of function via nonsense-mediated decay or canonical splice disruption. Details ▾Hide ▴
Evidence considered
- Missense substitution
- pvs1_variant_assessment confirms apply_generic_pvs1_framework=false
Sources
pvs1_variant_assessmentpvs1_gene_context
PM3 N/APM3 applies to recessive disorders where the variant is observed in trans with a pathogenic variant. No phasing data are available, and this criterion is not trivially assessable for this substitution. Details ▾Hide ▴
Evidence considered
- Not a trivially applicable criterion for this variant type
PM4 N/APM4 applies to in-frame deletions/insertions or stop-loss variants causing protein length change. This variant is a single-nucleotide substitution resulting in a missense change, not a protein length alteration. Details ▾Hide ▴
Evidence considered
- Missense substitution
- not a protein length-changing variant
PM5 N/ANo pathogenic missense variants have been identified at codon 194 (Ile194) to serve as comparator variants for PM5. Details ▾Hide ▴
Evidence considered
- PM5 candidate search: found=false
- no same-residue comparator variants
Sources
pm5_candidates
BP3 N/ABP3 applies to in-frame insertions/deletions in repetitive regions. This variant is a single-nucleotide substitution and does not involve an in-frame indel. Details ▾Hide ▴
Evidence considered
- Missense substitution
- not an in-frame indel
BP7 N/ABP7 applies only to synonymous (silent) variants with no predicted splicing impact. NM_018062.3:c.580A>G is a missense variant (p.Ile194Val) and is not synonymous. BP7 is not applicable. Details ▾Hide ▴
Evidence considered
- Missense substitution
- not synonymous
Identifiers
- Gene
- FANCL
- Transcript
- NM_018062.3
- Coding (HGVS c.)
- NM_018062.3:c.580A>G
- Protein (HGVS p.)
- NP_060532.2:p.(Ile194Val)
- GRCh38
- chr2:58165835 T>C
- GRCh37
- chr2:58392970 T>C
- ClinVar
- 840033
Gene diagram
Every interpreted variant in FANCL, mapped onto the exon structure of NM_018062.3. Select a row to find it on the plot.
FANCLNM_018062.3
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in FANCL
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
235 / 1,614,080 alleles
AF 0.000146 · 1 homozygotes · FAF 0.00119
gnomAD v2.1
68 / 282,780 alleles
AF 0.00024 · 0 homozygotes · FAF 0.00119
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 0.00015 · 235 / 1,614,080 alleles · 1 hom · FAF 0.0012
| South Asian126 / 91,078 | 0.0014 |
| African/African American26 / 75,026 | 0.00035 |
| Remaining individuals15 / 62,504 | 0.00024 |
| Middle Eastern1 / 6,060 | 0.00017 |
| East Asian6 / 44,870 | 0.00013 |
| Admixed American6 / 60,002 | 0.0001 |
| European (non-Finnish)54 / 1,179,986 | 4.6e-051 hom |
| European (Finnish)1 / 64,038 | 1.6e-05 |
0 alternate alleles recorded in 2 other groups: Amish, Ashkenazi Jewish.
gnomAD v2.1
AF 0.00024 · 68 / 282,780 alleles · 0 hom · FAF 0.0012
| South Asian47 / 30,612 | 0.0015 |
| African/African American7 / 24,970 | 0.00028 |
| East Asian5 / 19,950 | 0.00025 |
| Admixed American5 / 35,440 | 0.00014 |
| Remaining individuals1 / 7,222 | 0.00014 |
| European (non-Finnish)3 / 129,102 | 2.3e-05 |
0 alternate alleles recorded in 2 other groups: Ashkenazi Jewish, European (Finnish).
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000145594; MAF= 0.01456%, 235/1614080 alleles, homozygotes = 1) and has highest observed frequency in the South Asian population (AF= 0.00138343; MAF= 0.13834%, 126/91078 alleles, homozygotes = 0); grpmax FAF= 0.00118704.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00024047; MAF= 0.02405%, 68/282780 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.00153535; MAF= 0.15353%, 47/30612 alleles, homozygotes = 0); grpmax FAF= 0.00118549.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.049
- BayesDel
- -0.583
How the predictions were used
BP4 SupportingMultiple lines of computational evidence uniformly predict no impact on the gene product. REVEL score 0.049 (strongly benign-predicting), BayesDel score -0.583 (benign-predicting), and SpliceAI max delta 0.00 (no predicted splicing impact). All available in silico tools support a benign interpretation. Details ▾Hide ▴
Evidence considered
- REVEL 0.049 (benign
- well below 0.5 threshold)
- BayesDel -0.583 (benign
- well below 0.0 threshold)
- SpliceAI max delta 0.00 (no splice alteration predicted)
Sources
PP3 Multiple in silico predictors uniformly suggest a benign effect. REVEL score is 0.049 (benign-predicting, well below typical PP3 threshold of >0.5). BayesDel score is -0.583 (benign-predicting). SpliceAI predicts no splicing impact (max delta score 0.00). No computational tool supports a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL 0.049 (benign)
- BayesDel -0.583 (benign)
- SpliceAI max delta 0.00 (no splicing impact)
Sources
BP7 N/ABP7 applies only to synonymous (silent) variants with no predicted splicing impact. NM_018062.3:c.580A>G is a missense variant (p.Ile194Val) and is not synonymous. BP7 is not applicable. Details ▾Hide ▴
Evidence considered
- Missense substitution
- not synonymous
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.049. BayesDel score = -0.583145.
6 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
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PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Richards S et al. · 2015This is the ACMG/AMP 2015 standards and guidelines for variant interpretation. It provides the classification framework and does not discuss the FANCL c.580A>G variant.Does not name this variant
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PMID 18197057 ↗Carrier screening in individuals of Ashkenazi Jewish descent.Gross SJ et al. · 2008This is an ACMG practice guideline on carrier screening in individuals of Ashkenazi Jewish descent. It discusses general screening recommendations for Jewish genetic disorders and does not mention FANCL or the c.580A>G variant.Does not name this variant
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PMID 20301575 ↗Fanconi Anemia.Adam MP et al. · 1993GeneReviews chapter on Fanconi Anemia providing clinical and molecular overview of the disorder. No abstract content was retrieved; based on the title and source, this is a general disease summary that is unlikely to contain variant-specific data for c.580A>G.Does not name this variant
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PMID 26389210 ↗Genetics of Breast and Gynecologic Cancers (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002PDQ cancer genetics summary on Genetics of Breast and Gynecologic Cancers. No abstract content was retrieved; this is a general clinical reference that is unlikely to contain variant-specific data for FANCL c.580A>G.Does not name this variant
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PMID 26389258 ↗Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002PDQ cancer genetics summary on Cancer Genetics Risk Assessment and Counseling. No abstract content was retrieved; this is a general clinical reference unlikely to discuss the specific FANCL c.580A>G variant.Does not name this variant
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PMID 26389333 ↗Genetics of Skin Cancer (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002PDQ cancer genetics summary on Genetics of Skin Cancer. No abstract content was retrieved; this is a general clinical reference unlikely to discuss the specific FANCL c.580A>G variant.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
235 / 1,614,080 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
2 Uncertain significance
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/840033/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-58392970-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-58165835-T-C?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/2-58165835-T-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_018062.3%3Ac.580A…
- OncoKB ↗www.oncokb.org/gene/FANCL/I194V
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=FANCL+c.580A%3EG
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000145594; MAF= 0.01456%, 235/1614080 alleles, homozygotes = 1) and has highest observed frequency in the South Asian population (AF= 0.00138343; MAF= 0.13834%, 126/91078 alleles, homozygotes = 0); grpmax FAF= 0.00118704.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00024047; MAF= 0.02405%, 68/282780 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.00153535; MAF= 0.15353%, 47/30612 alleles, homozygotes = 0); grpmax FAF= 0.00118549.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 840033)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.049. BayesDel score = -0.583145.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. FANCL, an E3 ubiquitin ligase involved in DNA repair, is infrequently altered in cancer. Germline mutations of FANCL are associated with the cancer pr
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.